Clinically, ischemic stroke is recognized as a sexually dimorphic disease. Most international databases consistently demonstrate that women have lower stroke incidence relative to men until advanced age. However, elderly women have higher morbidity and mortality compared to age-matched men once a stroke occurs. Aging enhances the inflammatory response to stroke, and recent data demonstrate that this effect is significantly more pronounced in females. Reproductive hormones clearly contribute to such differences in male and female pathobiology, however, the hormonal environment does not fully account for ischemic sexual dimorphism as tissue damage and functional outcome after an induced stroke are influenced by biologic sex in addition to the hormonal milieu. Emerging data has shown that the mechanisms that trigger cell death differ in males and females. We will utilize genetically manipulated (Four Core Genotype) mice to dissociate the effects of chromosomal sex from that of gonadal hormones on stroke outcome in young animals (Aim 1); determine the effect of manipulating neonatal hormone levels on adult infarct damage (Aim 2); and investigate sex and hormone contributions to post-stroke inflammation in the 4CG mice (Aim 3) using a well established middle cerebral artery occlusion (MCAO) model of stroke. The overall goal of this proposal is to determine the genetic and hormonal (organizational and activational effects) contributions to stroke sensitivity across the lifespan. Identification of sex selective cell death mechanisms has significant translational relevance, as neuroprotective agents that are efficacious in one sex may exacerbate injury in the other. As recent clinical trials have shown variable efficacy of drugs in male and female patients, developing sex- specific therapeutic targets may improve our ability to treat stroke patients of both sexes. PUBLIC HEALTH RELEVANCE: There is considerable evidence from both clinical and experimental studies that outcomes after stroke differ in males and females. New experimental data has shown that brain cells die differently in the male versus the female brain, and each sex responds differently to neuroprotective strategies. As stroke is now the number one cause of disability, new treatments are urgently needed.